Project Summary/Abstract Because infertility is a growing public health problem, it is imperative that we understand the basic mechanisms and identify the genetic risk factors that give rise to this disease. The most common genetic abnormality that causes miscarriage is aneuploidy, an embryo with an improper number of chromosomes. While increased risk of aneuploidy is strongly correlated with increasing maternal age, significant variation exists in aneuploidy rates at any given age, making age alone an inadequate biomarker for the risk of producing an aneuploid conception. Therefore, we hypothesize that women who produce higher than average levels of preimplantation stage aneuploidy at a given age possess causal variants in genes which predispose them to an early risk of producing an aneuploid conception. To test this hypothesis, we will sequence the exomes of women at the extremes of the preimplantation aneuploidy phenotype. This project requires a significant number of prior achievements, including the creation of a DNA bank from women who have undergone in vitro fertilization (IVF) and comprehensive chromosome screening (CCS) of IVF-derived embryos, and the development and validation of an accurate method of CCS. Both of these hurdles have now been overcome making this proposal feasible. To achieve statistical power to accurately identify disease-causing genes, this study will complete exome-sequencing efforts that were initiated with pilot project funds. Previously identified candidate genes and those identified by sequencing in this project will be evaluated for functional significance in an animal model, because studies involving introduction of mutant genes are not possible in humans. These approaches will shed light on the molecular mechanisms that control chromosome segregation in female gametes. Ultimately, this study could lead to the identification of maternal genetic markers for risk of producing an aneuploid conception, and help prevent infertility by empowering women with necessary and personalized information to better preserve their individual fertility.